Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:4.1.1.6 (CAD)
4,420 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In 2010, gynecologic malignancies were the 4th leading cause of death in U.S. women and for patients with extensive primary or recurrent disease, treatment with interstitial brachytherapy may be an option. However, brachytherapy requires precise insertion of hollow catheters with introducers into the tumor in order to eradicate the cancer. In this study, a software solution to assist interstitial gynecologic brachytherapy has been investigated and the software has been realized as an own module under (3D) Slicer, which is a free open source software platform for (translational) biomedical research. The developed research module allows on-time processing of intra-operative magnetic resonance imaging (iMRI) data over a direct DICOM connection to a MR scanner. Afterwards follows a multi-stage registration of CAD models of the medical brachytherapy devices (template, obturator) to the patient's MR images, enabling the virtual placement of interstitial needles to assist the physician during the intervention.
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PMID:Development of an open source software module for enhanced visualization during MR-guided interstitial gynecologic brachytherapy. 2479 Aug 16

The acid-sensitive PEGylated doxorubicin (DOX) with exact chemical structure was designed and prepared as a potential tumor intracellular microenvironment-responsive drug delivery system. First, the insensitive succinic anhydride-functionalized DOX (i.e., SAD) and acid-sensitive cis-aconitic anhydride-modified DOX (i.e., CAD) were synthesized through the ring-opening reaction. Subsequently, the insensitive and acid-sensitive PEGylated DOX (i.e., mPEG-SAD and mPEG-CAD) was prepared by the condensation reaction between the terminal hydroxyl group of mPEG and the carboxyl group in SAD and CAD, respectively. The obtained mPEG-SAD and mPEG-CAD could spontaneously self-assemble into micelles in phosphate-buffered saline at pH 7.4 with diameters of about 100 nm. The DOX release of mPEG-CAD micelle could be accelerated by the decrease of pH from 7.4, 6.8, to 5.5 in relation to that of mPEG-SAD micelle. On the other hand, the result of the cellular proliferation inhibition test indicated that mPEG-CAD micelle exhibited favorable antiproliferative activity in vitro. In addition, the selective intratumoral accumulation and antitumor efficacy of mPEG-CAD micelle were significantly better than those of free DOX and mPEG-SAD. More importantly, the prodrug micelles exhibited upregulated security in vivo as compared to free DOX. Overall, the mPEG-CAD micelle with enhanced antitumor efficacy and decreased side effects was a fascinating prospect for the clinical chemotherapy of malignancy.
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PMID:Preclinical evaluation of antitumor activity of acid-sensitive PEGylated doxorubicin. 2541 51

CAD and cancer account for over one-half of all deaths in the world. It is claimed that the 21st century is the last century for CAD. This is, in part, because CAD is preventable based on randomized, placebo-controlled clinical trials, which show modifying known risk factors such as cholesterol is associated consistently with 40-60% reduction in morbidity and mortality from CAD. Comprehensive prevention will require modifying genetic risk factors that are claimed to account for 40-60% of predisposition to CAD. The 21st century is meeting this challenge with over 50 genetic risk variants discovered and replicated in large genome-wide association studies involving over 200,000 cases and controls. Similarly, 157 genetic variants have been discovered that regulate plasma lipids including, LDL-C, HDL-C, triglycerides, and total cholesterol. A major finding from these studies is that only 15 of the 50 genetic variants for CAD act through known risk factors. Hence, the pathogenesis of CAD in addition to cholesterol and other known risk factors is due to various other factors, many of which remain unknown. Secondly, genes regulating the plasma triglyceride levels are strongly associated with the pathogenesis of CAD. Thirdly, Mendelian randomization studies show no protection from genes that increase plasma HDL cholesterol. This is contrary to current opinion. These genetic risk variants have provided new targets for the development of novel therapies to prevent CAD. Already a new and potent drug has been developed targeting PCSK9, which is in phase 3 clinical trials and shows great efficacy and safety for prevention of CAD. The 21st century is looking very bright for the prevention of CAD.
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PMID:A genetic basis for coronary artery disease. 2557 17

Scorzonera hispanica commonly known as black salsify is a perennial herbaceous plant belonging to the Asteraceae family. The subaerial parts of black salsify are cultivated in Central and Southern Europe as a vegetable. There are only few reports on the chemical composition of S.hispanica. The aim of the present study was to determine the chemical composition of subaerial and aerial parts of this species. In total, twelve compounds were isolated and identified with spectroscopic methods, including a series of seven rare sesquiterpenoids - five bisabolane and two curcumenal derivatives. Furthermore, a fully validated HPLC-DAD-CAD method for the quantification of phenolic compounds of S. hispanica was developed. The cytotoxicities of lignan [(-)-syringaresinol (1)] and bisabolane derivatives from S. hispanica against several cancer cell lines were studied. (-)-Syringaresinol was the only compound active against myeloma cell lines and was also active against colon cancer cell lines. However, this lignan was also found to be cytotoxic for normal peripheral blood mononuclear cells (PBMCs). Two bisabolane derivatives were active against colon cancer cell lines and may be interesting as lead structures for the development of new anti-colon cancer agents.
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PMID:Qualitative and quantitative analyses of secondary metabolites in aerial and subaerial of Scorzonera hispanica L. (black salsify). 2546 29

The reversible PEGylation endows antitumor drugs with various fascinating advantages, including prolonged circulation time in blood, enhanced accumulation in tumor tissue, increased cellular uptake, and promoted intracellular drug release, to improve the therapeutic efficacy and security. Here, the obtained succinic anhydride (SA)-functionalized DOX (SAD) (i.e., insensitive succinic anhydride-functionalized doxorubicin (DOX)) and aconitic anhydride (CA)-modified DOX (CAD) (i.e., acid-sensitive cis-aconitic anhydride-modified DOX) are conjugated to the terminal of poly(ethylene glycol) (PEG) yielding the unresponsive SAD-PEG-SAD and pH-responsive CAD-PEG-CAD prodrugs, respectively. The prepared prodrugs can self-assemble into micelles in aqueous solution. Both micelles are sufficiently stable at normal physiological pH (i.e., 7.4), while CAD-PEG-CAD micelle gradually swells and finally disassembles at intratumoral (i.e., 6.8) and especially endosomal pHs (i.e., 5.5). DOX release from CAD-PEG-CAD at pH 7.4 is efficiently inhibited, whereas it is significantly accelerated by the rapid cleavage of amide bond at pH 5.5. In addition, CAD-PEG-CAD exhibits more efficient cellular uptake and potent cytotoxicity in vitro, as well as improved tissue distribution and superior tumor suppression in vivo than free DOX and SAD-PEG-SAD. More importantly, the PEGylated DOX exhibits favorable security in vivo. In brief, the smart CAD-PEG-CAD with enhanced antitumor efficacy and decreased side effects shows as a promising powerful platform for the clinical chemotherapy of malignancy.
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PMID:pH-Responsive Reversible PEGylation Improves Performance of Antineoplastic Agent. 2564 3

Cancer cells reorganize their metabolic pathways to fuel demanding rates of proliferation. Oftentimes, these metabolic phenotypes lie downstream of prominent oncogenes. The lipid signaling molecule phosphatidic acid (PtdOH), which is produced by the hydrolytic enzyme phospholipase D (PLD), has been identified as a critical regulatory molecule for oncogenic signaling in many cancers. In an effort to identify novel regulatory mechanisms for PtdOH, we screened various cancer cell lines, assessing whether treatment of cancer models with PLD inhibitors altered production of intracellular metabolites. Preliminary findings lead us to focus on how deoxyribonucleoside triphosphates (dNTPs) are altered upon PLD inhibitor treatment in gliomas. Using a combination of proteomics and small molecule intracellular metabolomics, we show herein that PtdOH acutely regulates the production of these pyrimidine metabolites through activation of CAD via mTOR signaling pathways independently of Akt. These changes are responsible for decreases in dNTP production after PLD inhibitor treatment. Our data identify a novel regulatory role for PLD activity in specific cancer types.
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PMID:Human phospholipase D activity transiently regulates pyrimidine biosynthesis in malignant gliomas. 2564 64

Large defects of the human face often cause esthetic as well as functional disorders. We present a new technique for reconstruction of the mandible with prosthodontic rehabilitation in a single surgery, using the implant-supported, bar-retained overdenture as an external fixator. A 58-year-old patient presented with a near total defect of the mandible after cancer resection. For rehabilitation, the mandibular condyles were virtually positioned in the centre of the fossae, and four dental implants were planned. The position of the fibula segments as well as their angulation and lengths were adapted to the implant position. To transfer this plan into surgery, a combined cutting/implant drilling guide was computer-aided printed. To provide the correct angulation of the fibula segments, a CAD/CAM dental arch-bar was made from titanium, fulfilling three functions: to bear the provisional prosthesis; to stabilize the molded fibula as an external fixator; and to position the complete fibula with the prosthesis in a correct relation to the upper jaw and occlusion, as indicated by the prosthesis. This innovative approach of combined prosthodontic and reconstructive rehabilitation could shorten the total reconstruction/rehabilitation time and avoid the need for additional extended surgeries.
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PMID:A bar-retained overdenture as an external fixator device in a three-dimensional CAD/CAM-based surgical reconstruction of the mandible. 2624 97

Phosphorylation events within cancer cells often become dysregulated, leading to oncogenic signaling and abnormal cell growth. Phosphopeptides derived from aberrantly phosphorylated proteins that are presented on tumors and not on normal tissues by human leukocyte antigen (HLA) class I molecules are promising candidates for future cancer immunotherapies, because they are tumor specific and have been shown to elicit cytotoxic T cell responses. Robust phosphopeptide enrichments that are suitable for low input amounts must be developed to characterize HLA-associated phosphopeptides from clinical samples that are limited by material availability. We present two complementary mass spectrometry-compatible, iron(III)-immobilized metal affinity chromatography (IMAC) methods that use either nitrilotriacetic acid (NTA) or iminodiacetic acid (IDA) in-house-fabricated columns. We developed these protocols to enrich for subfemtomole-level phosphopeptides from cell line and human tissue samples containing picograms of starting material, which is an order of magnitude less material than what is commonly used. In addition, we added a peptide esterification step to increase phosphopeptide specificity from these low-input samples. To date, hundreds of phosphopeptides displayed on melanoma, ovarian cancer, leukemia and colorectal cancer have been identified using these highly selective phosphopeptide enrichment protocols in combination with a program called 'CAD Neutral Loss Finder' that identifies all spectra containing the characteristic neutral loss of phosphoric acid from phosphorylated serine and threonine residues. This methodology enables the identification of HLA-associated phosphopeptides presented by human tissue samples containing as little as nanograms of peptide material in 2 d.
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PMID:Complementary IMAC enrichment methods for HLA-associated phosphopeptide identification by mass spectrometry. 2624 97

Cancer cells hijack and remodel existing metabolic pathways for their benefit. Argininosuccinate synthase (ASS1) is a urea cycle enzyme that is essential in the conversion of nitrogen from ammonia and aspartate to urea. A decrease in nitrogen flux through ASS1 in the liver causes the urea cycle disorder citrullinaemia. In contrast to the well-studied consequences of loss of ASS1 activity on ureagenesis, the purpose of its somatic silencing in multiple cancers is largely unknown. Here we show that decreased activity of ASS1 in cancers supports proliferation by facilitating pyrimidine synthesis via CAD (carbamoyl-phosphate synthase 2, aspartate transcarbamylase, and dihydroorotase complex) activation. Our studies were initiated by delineating the consequences of loss of ASS1 activity in humans with two types of citrullinaemia. We find that in citrullinaemia type I (CTLN I), which is caused by deficiency of ASS1, there is increased pyrimidine synthesis and proliferation compared with citrullinaemia type II (CTLN II), in which there is decreased substrate availability for ASS1 caused by deficiency of the aspartate transporter citrin. Building on these results, we demonstrate that ASS1 deficiency in cancer increases cytosolic aspartate levels, which increases CAD activation by upregulating its substrate availability and by increasing its phosphorylation by S6K1 through the mammalian target of rapamycin (mTOR) pathway. Decreasing CAD activity by blocking citrin, the mTOR signalling, or pyrimidine synthesis decreases proliferation and thus may serve as a therapeutic strategy in multiple cancers where ASS1 is downregulated. Our results demonstrate that ASS1 downregulation is a novel mechanism supporting cancerous proliferation, and they provide a metabolic link between the urea cycle enzymes and pyrimidine synthesis.
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PMID:Diversion of aspartate in ASS1-deficient tumours fosters de novo pyrimidine synthesis. 2656 30

CRIM1 is a member of the bone morphogenetic protein (BMP) antagonists; however, the role of CRIM1 in controlling cancer cell behavior remains unknown. This study investigated its function in the A549 cell line in vitro. The results show that treating cells with CRIM1 peptide could increase the migration and adhesion of A549. Consistently, silencing the CRIM1 expression decreased the migration and adhesion of A549. Furthermore, the CRIM1 protein expression was increased in A549 which were treated with transforming growth factor beta 1 to induced EMT. However, CRIM1 peptide treatment could increase the expression of N-CAD and E-CAD expression. Finally, overexpression of the oncogene YAP1 resulted in an up-regulation of the CRIM1 expression in A549, suggesting that CRIM1 was a target of the Hippo pathway. These observations provide evidence for the first time that CRIM1 plays a role in cancer cells by enhancing the migration and adhesion and increasing the expression of N-CAD and E-CAD.
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PMID:CRIM1, a newfound cancer-related player, regulates the adhesion and migration of lung cancer cells. 2665 68


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